Neurological disorders afflict large numbers of people in the world. In disorders ranging from neurodegenerative diseases (e.g., Alzheimer's and Parkinson's diseases) to traumatic spinal cord injuries, there is a need for molecules that promote neuronal growth. While some proteins are known that can stimulate neuronal growth, few small molecules are known that can stimulate neuronal growth.
Chondroitin sulfate (CS) glycosaminoglycans are sulfated polysaccharides implicated in cell division, neuronal development, and spinal cord injury (Mizuguchi, S.; Uyama, T.; Kitagawa, H.; Nomura, K. H.; Dejima, K.; Gengyo-Ando, K.; Nitani, S.; Sugahara, K.; Nomura, K. Nature 2003, 423, 443-448; Sugahara, K.; Mikami, T.; Uyama, T.; Mizuguchi, S.; Nomura, K.; Kitagawa, H. Curr. Op. Chem. Biol. 2003, 13, 612-620; Bradbury, E. J.; Moon, L. D. F.; Popat, R. J.; King, V. R.; Bennett, G. S.; Patel, P. N.; Fawcett, J. W.; McMahon, S. B. Nature 2002, 416, 636-640.). As with all glycosaminoglycans, the complexity and heterogeneity of Chondroitin sulfate (CS) glycosaminoglycans have hampered efforts to understand its precise biological roles. For instance, CS has been shown to prevent the growth of axons; yet it is also found in developing, growth-permissive regions. (Bradbury et al., supra; Emerling, D. E.; Lander, A. D. Neuron 1996, 17, 1089-1100). CS polysaccharides have been shown both to stimulate and to attenuate the growth of cultured neurons. (Brittis, P. A. et al. Science 1992, 255, 733-736; Dou, C. L.; Levine, J. M. J. Neurosci. 1995, 15, 8053-8066; Nadanaka, S. et al. J. Biol. Chem. 1998, 273, 3296-3307.) Notably, the molecules used in those studies were ˜200 saccharides in length, poorly defined, and heterogeneously sulfated, features that might account for the contradictory observations.
In addition, CS having a particular sulfation pattern (CS-E) is found on the protein appican, an isoform of the amyloid precursor protein that exhibits neurotrophic activity (Tsuchida, K. et al. J. Biol. Chem. 2001, 276, 37155-37160). Moreover, polysaccharides enriched in the CS-E motif have been shown to promote the outgrowth of neurons (Nadanaka, S. et al. J. Biol. Chem. 1998, 273, 3296-3307).
Because of the interest in studying neuronal growth and differentiation, there is a need for small molecule modulators of neuronal growth.